Diabetes results from the occurrence of one or more of several causative factors, and is characterized by an abnormal elevation in levels of plasma glucose (hyperglycemia). Persistent or uncontrolled hyperglycemia results in an increased probability of premature morbidity and mortality. Abnormal glucose homeostasis is usually associated with changes in the lipid, lipoprotein and apolipoprotein metabolism, or due to other metabolic and hemodynamic diseases.
Patients afflicted with Type-2 diabetes mellitus or noninsulin dependent diabetes mellitus (NIDDM), are especially at increased risk of suffering from macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy and retinopathy. Therapeutic control of glucose homeostasis, lipid metabolism and hypertension are critical in the clinical management and treatment of Type-2 diabetes mellitus.
The currently available therapeutics for treating available Type-2 diabetes, although effective, have recognized limitations. Compounds based on sulfonylureas (e.g. tolbutamide, glipizide, etc.), which stimulate the pancreatic beta-cells to secrete more insulin, are limited by the development of inhibitor resistant tissues, causing them to become inefficient or ineffective, even at high doses. Biguanide compounds, on the other hand, increase insulin sensitivity so as to cause correction of hyperglycemia to some extent. However, clinically used biguanides such as phenformin and metformin can induce side-effects such as lactic acidosis, nausea and diarrhea.
The more recent glitazone-type compounds (i.e. 5-benzylthiazolidine-2,4-diones) substantially increase insulin sensitivity in muscle, liver and adipose tissue resulting in either partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia. Currently used glitazones are agonists of the peroxisome proliferator activated receptor (PPAR), which is attributed to be responsible for their improved insulin sensitization. However, serious side effects (e.g. liver toxicity) have been known to occur with some glitazones such as, for example, troglitazone. Compounds that are inhibitors of the dipeptidyl peptidase-IV (“DPP-IV”, “DPP-4” or “DP-IV”) enzyme are also under investigation as drugs that may be useful in the treatment of diabetes, and particularly Type-2 diabetes. See for example, WO 97/40832, WO 98/19998, and U.S. Pat. No. 5,939,560.
DPP-IV is a membrane bound non-classical serine aminodipeptidase which is located in a variety of tissues (intestine, liver, lung, kidney) as well as on circulating T-lymphocytes (where the enzyme is known as CD-26). It is responsible for the metabolic cleavage of certain endogenous peptides (GLP-1(7-36), glucagon) in vivo and has demonstrated proteolytic activity against a variety of other peptides (e.g. GHRH, NPY, GLP-2, VIP) in vitro.
The usefulness of DPP-IV inhibitors in the treatment of Type-2 diabetes is based on the fact that DPP-IV in vivo readily inactivates glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 (7-36) is a 29 amino-acid peptide derived by post-translational processing of proglucagon in the small intestine. GLP-1(7-36) has multiple actions in vivo including the stimulation of insulin secretion, inhibition of glucagon secretion, the promotion of satiety, and the slowing of gastric emptying. Based on its physiological profile, the actions of GLP-1(7-36) are expected to be beneficial in the prevention and treatment of Type-2 diabetes, and potentially obesity. To support this claim, exogenous administration of GLP-1(7-36) (continuous infusion) in diabetic patients has demonstrated efficacy in this patient population. GLP-1(7-36) is degraded rapidly in vivo and has been shown to have a short half-life in vivo (t1/2 of about 1.5 min). Based on a study of genetically bred DPP-IV KO mice and on in vivo/in vitro studies with selective DPP-IV inhibitors, DPP-IV has been shown to be the primary degrading enzyme of GLP-1(7-36) in vivo. GLP-1(7-36) is degraded by DPP-IV efficiently to GLP-1(9-36), which has been speculated to act as a physiological antagonist to GLP-1(7-36). Inhibition of DPP-IV in vivo should, therefore, potentiate endogenous levels of GLP-1(7-36) and attenuate formation of its antagonist GLP-1(9-36) and serve to ameliorate the diabetic condition.
GLP-1 and GIP are incretins that are produced upon ingestion of food, and which stimulate production of insulin. Inhibition of DPP-IV causes decreased inactivation of the incretins, which in turn, results in an increase in their effectiveness in stimulating pancreatic production of insulin. DPP-IV inhibition therefore, results in an increase in the level of serum insulin. Since the incretins are produced upon consumption of food only, DPP-IV inhibition is not expected to increase insulin levels when not required, thereby precluding excessive lowering of blood sugar (hypoglycemia). Inhibition of DPP-IV, is therefore, is expected to increase insulin levels without increasing the risk of hypoglycemia, thereby lowering deleterious side effects associated with currently used insulin secretagogues. Although DPP-IV inhibitors have not been studied extensively as therapeutics for diseases other than diabetes, they are expected to have other potential therapeutic utilities.